Repetitive head impacts (RHI) are associated with the neurodegenerative disease, chronic traumatic encephalopathy (CTE). According to research diagnostic criteria for CTE, known as Traumatic Encephalopathy Syndrome (TES), CTE presents with behavior, mood, and/or cognitive symptoms. There is diversity in the presence of symptoms due to differences in pathology and brain regions affected, and mechanisms of the later-life clinical deficits from RHI are ill-defined. As a result, long-term neurological diseases from RHI (e.g., CTE) cannot be detected at this time. White matter signal abnormalities (WMSA) are non-specific magnetic resonance imaging (MRI) markers of pathologies that may be associated with RHI and affect the clinical presentation of CTE. WMSA predict increased risk for Alzheimer's disease (AD) and pathological correlates of WMSA are common in CTE. Our published data linked T1 WMSA with RHI and executive deficits in former National Football League (NFL) players, independent of vascular status. However, multi-modal neuroimaging studies with control and comparison (e.g., AD) groups are needed to clarify the presence, nature, and effects of WMSA in former NFL players. This K23 will use fluid attenuated inversion recovery (FLAIR) and diffusion MRI to examine WMSA as a long-term consequence of RHI that are distinct from AD and affect later-life clinical function. A team of transdisciplinary scientists from Boston University (BU) will address Dr. Alosco's knowledge gaps in areas key for the study of CTE (exposure science, neuroimaging, neuropathology), leading to an R01 to launch his own research program. The K23 will include 30 male symptomatic former NFL players (45-74 years), 30 same-age and vascular risk-matched male normal controls (NC), and 30 same-age and vascular-risk matched males with AD. NC and AD subjects will be without head trauma history. Former NFL players and NC will be from Dr. Stern's (primary mentor) NINDS U01 examining CTE biomarkers. AD subjects will be from the BU AD and CTE Center (ADCTEC) Registry. The ADCTEC outreach core will ensure inclusion of young AD males (45-55 years). All subjects complete medical, cognitive, behavior/mood, neuroimaging evaluations (T1, FLAIR, diffusion, PET), and lumbar puncture, and blood draw. FreeSurfer and Tracts Constrained by Underlying Anatomy will assess lobar volumes and fiber paths. WMSA will be estimated via a Bayesian probability structure. We will test if former NFL players have a distinct pattern of lobar and fiber path WMSA relative to NC and AD, and if regional WMSA predict cognitive, behavior, and mood function. We will examine whether RHI predicts WMSA and fiber path dysintegrity. In the former NFL players, we will test whether WMSA correspond to lobar volume loss and fiber path dysintegrity and explore if WMSA are related to fluid and PET markers of tau. Millions of Americans are exposed to RHI and this study will have a major public health impact by improving knowledge on the neurological sequelae of RHI, which is imperative to facilitate research on the diagnosis, treatment, and prevention of brain diseases, like CTE.